Project Summary The long-term goal of this research program is to determine the genetic and molecular mechanisms that cause spontaneous and induced mutations to show different effects across genetically distinct individuals. These `background effects' are important to human health because they can complicate efforts to predict, prevent, and treat disease based on personalized genomic data. Although background effects are known to result from genetic interactions between mutations and standing polymorphisms, their underlying genetic architectures and molecular mechanisms have only begun to be characterized. Our recent work in budding yeast suggests that background effects are typically caused by multiple loci that interact not only with a mutation, but also each other. This finding could have important implications for efforts to map the genetic basis of diseases and other traits that are commonly influenced by mutations, and thus its generality and underlying mechanisms require deeper investigation. Here, we will extend our work on background effects in yeast using emerging technologies for high-throughput phenotyping and genome editing, as well as statistically powerful linkage mapping. Our work will address three main questions: (1) What are the prevalence and forms of background effects? (2) What genetic complexities and types of epistasis underlie background effects? And, (3) what are the properties of genes and genetic variants that cause background effects? This work will produce detailed insights into background effects that should advance efforts to understand and predict the relationship between genotype and phenotype in humans and model organisms.